Abstract
Virtual screening of an in-house virtual library of synthetic compounds using FlexX, followed by enzyme inhibition, identified hydrazide and hydrazine derivatives as novel aspartic protease inhibitors. These compounds inhibited human cathepsin D and Plasmodium falciparum plasmepsin-II with low micromolar concentrations (IC(50) = 1-2.5 microM). Modelling studies with plasmepsin-II predicted binding of ligands at the centre of the extended substrate-binding cleft, where hydrazide/hydrazine parts of the inhibitors acted as the transition state mimic by forming electrostatic interactions with catalytic aspartates.
MeSH terms
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Antimalarials / chemical synthesis
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Antimalarials / chemistry
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Antimalarials / metabolism
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / chemistry
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Aspartic Acid Endopeptidases / metabolism
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Benzhydryl Compounds / chemical synthesis
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Benzhydryl Compounds / chemistry
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Benzhydryl Compounds / metabolism
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Catalytic Domain
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Cathepsin D / antagonists & inhibitors
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Cathepsin D / metabolism
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Databases, Factual
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Drug Evaluation, Preclinical
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Humans
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Hydrazines / chemical synthesis
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Hydrazines / chemistry*
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Hydrazines / metabolism*
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Models, Molecular
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Molecular Conformation
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Osmolar Concentration
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Phenylhydrazines / chemical synthesis
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Phenylhydrazines / chemistry
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Phenylhydrazines / metabolism
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Plasmodium falciparum / enzymology
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry*
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Protease Inhibitors / metabolism*
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Protein Interaction Domains and Motifs
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Protozoan Proteins / antagonists & inhibitors
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Protozoan Proteins / chemistry
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Protozoan Proteins / metabolism
Substances
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Antimalarials
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Benzhydryl Compounds
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Hydrazines
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Phenylhydrazines
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Protease Inhibitors
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Protozoan Proteins
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1,2-diphenylhydrazine
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Aspartic Acid Endopeptidases
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plasmepsin II
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CTSD protein, human
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Cathepsin D